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(Image caption: Multiple synapse heads send out filopodia (green) converging on one microglia (red), as seen by focused ion beam scanning electron microscopy (FIBSEM). Credit: L. Weinhard, EMBL Rome)

Captured on film for the first time: microglia nibbling on brain synapses

For the first time, EMBL researchers have captured microglia nibbling on brain synapses. Their findings show that the special glial cells help synapses grow and rearrange, demonstrating the essential role of microglia in brain development. Nature Communications publishes the results on March 26.

Around one in ten cells in your brain are microglia. Cousins of macrophages, they act as the first and main contact in the central nervous system’s active immune defense. They also guide healthy brain development. Researchers have proposed that microglia pluck off and eat synapses - connections between brain cells - as an essential step in the pruning of connections during early circuit refinement. But, until now, no one had seen them do it.

Microglia make synapses stronger

That is why Laetitia Weinhard, from the Gross group at EMBL Rome, set out on a massive imaging study to actually see this process in action in the mouse brain, in collaboration with the Schwab team at EMBL Heidelberg. “Our findings suggest that microglia are nibbling synapses as a way to make them stronger, rather than weaker,” says Cornelius Gross, who led the work.

Warm welcome

The team saw that around half of the time that microglia contact a synapse, the synapse head sends out thin projections or ‘filopodia’ to greet them. In one particularly dramatic case – as seen in the accompanying image – fifteen synapse heads extended filopodia toward a single microglia as it picked on a synapse. “As we were trying to see how microglia eliminate synapses, we realised that microglia actually induce their growth most of the time,” Laetitia Weinhard explains.

It turns out that microglia might underly the formation of double synapses, where the terminal end of a neuron releases neurotransmitters onto two neighboring partners instead of one. This process can support effective connectivity between neurons. Weinhard: “This shows that microglia are broadly involved in structural plasticity and might induce the rearrangement of synapses, a mechanism underlying learning and memory.”

Perseverance

Since this was the first attempt to visualise this process in the brain, the current paper entails five years of technological development. The team tried three different state-of-the-art imaging systems before they succeeded. Finally, by combining correlative light and electron microscopy (CLEM) and light sheet fluorescence microscopy - a technique developed at EMBL - they were able to make the first movie of microglia eating synapses.

me:

college teacher:

I’m writing this post about the upcoming midterm elections on November 6th, in which I’ll be voting in the state of Tennessee. In the past I’ve been reluctant to publicly voice my political opinions, but due to several events in my life and in the world in the past two years, I feel very differently about that now.  I always have and always will cast my vote based on which candidate will protect and fight for the human rights I believe we all deserve in this country. I believe in the fight for LGBTQ rights, and that any form of discrimination based on sexual orientation or gender is WRONG. I believe that the systemic racism we still see in this country towards people of color is terrifying, sickening and prevalent.

I cannot vote for someone who will not be willing to fight for dignity for ALL Americans, no matter their skin color, gender or who they love.  Running for Senate in the state of Tennessee is a woman named Marsha Blackburn. As much as I have in the past and would like to continue voting for women in office, I cannot support Marsha Blackburn. Her voting record in Congress appalls and terrifies me. She voted against equal pay for women. She voted against the Reauthorization of the Violence Against Women Act, which attempts to protect women from domestic violence, stalking, and date rape. She believes businesses have a right to refuse service to gay couples. She also believes they should not have the right to marry. These are not MY Tennessee values. I will be voting for Phil Bredesen for Senate and Jim Cooper for House of Representatives.  Please, please educate yourself on the candidates running in your state and vote based on who most closely represents your values. For a lot of us, we may never find a candidate or party with whom we agree 100% on every issue, but we have to vote anyway.

Parkinson’s Gene Initiates Disease Outside of the Brain

Until very recently, Parkinson’s had been thought a disease that starts in the brain, destroying motion centers and resulting in the tremors and loss of movement. New research published this week in the journal Brain, shows the most common Parkinson’s gene mutation may change how immune cells react to generic infections like colds, which in turn trigger the inflammatory reaction in the brain that causes Parkinson’s. The research offers a new understanding of Parkinson’s disease.                                                    

“We know that brain cells called microglia cause the inflammation that ultimately destroys the area of the brain responsible for movement in Parkinson’s,” said Richard Smeyne, PhD, Director of the Jefferson Comprehensive Parkinson’s Disease and Movement Disorder Center at the Vickie and Jack Farber Institute for Neuroscience. “But it wasn’t clear how a common inherited mutation was involved in that process, and whether the mutation altered microglia.”

Together with Dr. Smeyne, first author Elena Kozina, PhD, looked at the mutant version of the LRRK2 gene (pronounced ‘lark’). Mutations in the LRRK2 gene are the most common cause of inherited Parkinson’s disease and are found in 40 percent of people of North African Arab descent and 18 percent of people of Ashkenazi Jewish descent with Parkinson’s. However there’s been controversy around the exact function of the LRRK2 gene in the brain.

“We know that gene mutation is not enough to cause the disease,” said Dr. Kozina, Post-Doctoral student at Jefferson (Philadelphia University + Thomas Jefferson University). “We know that twins who both carry the mutation, won’t both necessarily develop Parkinson’s. A second ‘hit’ or initiating event is needed.”

Based on his earlier work showing that the flu might increase risk of Parkinson’s disease, Dr. Smeyne decided to investigate whether that second hit came from an infection. Suspecting that the LRRK2 mutations might be acting outside of the brain, the researchers used an agent – the outer shell of bacteria, called lippopolysaccharide (LPS) – that causes an immune reaction. LPS itself does not pass into the brain, nor do the immune cells it activates, which made it ideal for testing whether this second hit was acting directly in the brain.

When the researchers gave the bacterial fragments to the mice carrying the two most common LRRK2 gene mutations, the immune reaction became a “cytokine storm,” with inflammatory mediators rising to levels that 3-5 times higher than a normal reaction to LPS. These inflammatory mediators were produced by T and B immune cells expressing the LRRK2 mutation.

Despite the fact that LPS did not cross the blood-brain barrier, the researchers showed that the elevated cytokines were able to enter the brain, creating an environment that caused the microglia to activate pathologically and destroy the brain region involved in movement.